T-Dxd improves PFS vs T-DM1 in second-line HER2-positive mBC treatment

Trastuzumab deruxtecan (T-Dxd) provides a highly clinically meaningful and statistically significant improvement in progression-free survival (PFS) vs trastuzumab emtansine (T-DM1) in second-line treatment of HER2-positive metastatic breast cancer (mBC), results of the phase III DESTINY-Breast03 trial have shown.

“These data, along with the encouraging trend for overall survival [OS] and higher objective response rate [ORR] with T-Dxd, and the comparable safety profile between the two groups, support T-Dxd to become the standard of care [SoC] for second-line treatment of HER2-positive mBC,” said investigator Dr Javier Cortés of the International Breast Cancer Center (IBCC), Quiron Group, Barcelona, Spain, who reported the results at the European Society for Medical Oncology (ESMO) Congress 2021. [Cortés J, et al, ESMO 2021, abstract LBA1]

In this first randomized phase III trial of T-Dxd in breast cancer, 524 patients with unresectable or metastatic HER2-positive disease previously treated with trastuzumab and taxane were randomized to receive open-label treatment with T-Dxd (5.4 mg/kg Q3W; n=261; median age, 54.3 years; from Asia, 57.1 percent) or T-DM1 (3.6 mg/kg Q3W; n=263; median age, 54.2 years; from Asia, 60.8 percent). At baseline, 50.2 percent of patients in the T-Dxd group vs 51 percent in the T-DM1 group had hormone receptor–positive disease, 23.8 percent vs 19.8 percent had brain metastases, 70.5 percent vs 70.3 percent had visceral disease, and 62.1 percent vs 60.1 percent had received prior pertuzumab therapy.

Highly significant PFS improvement

At interim analysis, the independent data monitoring committee recommended unblinding of the trial as the efficacy boundary for superiority in PFS was met.

“After a median follow-up of 15.5 months in the T-Dxd group and 13.9 months in the T-DM1 group, the primary endpoint of PFS by blinded independent central review had not reached median in the T-Dxd group and was at a median of 6.8 months in the T-DM1 group, while 12-month PFS rate was 75.8 percent vs 34.1 percent. The hazard ratio [HR] was 0.28 [95 percent confidence interval (CI), 0.22 to 0.37], with a p value of 7.8 x 10^-22,” reported Cortés.

“The PFS curves separated early, at the first scan after [initiation of] treatment, and persisted throughout,” he added.

The PFS benefit of T-Dxd vs T-DM1 was consistent in key subgroups, regardless of hormone receptor status (positive: HR, 0.3191; 95 percent CI, 0.2217 to 0.4594) (negative: HR, 0.2965; 95 percent CI, 0.2008 to 0.4378), presence or absence of prior pertuzumab therapy (HR, 0.3050 [95 percent CI, 0.2185 to 0.4257] and 0.2999 [95 percent CI, 0.1924 to 0.4675], respectively), presence or absence of visceral disease (HR, 0.2806 [95 percent CI, 0.2083 to 0.3779] and 0.3157 [95 percent CI, 0.1718 to 0.5804], respectively), number of prior lines of therapy (0–1: HR, 0.3302; 95 percent CI, 0.2275 to 0.4794) (≥2: HR, 0.2828; 95 percent CI, 0.1933 to 0.4136), and presence or absence of brain metastases (HR, 0.3796 [95 percent CI, 0.2267 to 0.6357] and 0.2665 [95 percent CI, 0.1939 to 0.3665], respectively).

OS and ORR results

Median OS was not estimable in both groups, while 12-month OS rate was 94.1 percent with T-Dxd vs 85.9 percent with T-DM1 (HR, 0.56; 95 percent CI, 0.36 to 0.86). “The p value of 0.007172 did not reach the prespecified cut-off for statistical significance [ie, p<0.000265], likely due to immature follow-up,” said Cortés.

“A majority of patients in the T-Dxd group had a reduction in tumour size. The ORR was 79.7 percent in the T-Dxd group vs 34.2 percent in the T-DM1 group, with complete response achieved in 16.1 percent vs 8.7 percent of the patients,” he continued.

Comparable safety profile vs T-DM1

“The safety profile of T-Dxd was consistent with previous data, with most adverse events [AEs] being haematological or gastrointestinal,” he reported. “Grade ≥3 drug-related treatment-emergent AEs [TEAEs] were reported in 45.1 percent vs 39.8 percent of patients in the T-Dxd vs T-DM1 group, while serious drug-related TEAEs occurred in 10.9 percent vs 6.1 percent of the patients.”

Drug-related TEAEs associated with treatment discontinuation and dose reduction were reported in 12.8 percent vs 5 percent and 21.4 percent vs 12.6 percent of the patients, respectively, but none were associated with death. “The most common TEAEs associated with treatment discontinuation and dose reduction for T-Dxd were interstitial lung disease [ILD]/pneumonitis [8.2 percent] and nausea [6.2 percent], respectively,” said Cortés.

While ILD/pneumonitis was more common with T-Dxd vs T-DM1 (any grade, 10.5 percent vs 1.9 percent), grade 3 events occurred in only 0.8 percent of patients in the T-Dxd group (vs 0 percent in the T-DM1 group), with no grade 4/5 events reported.

Left ventricular ejection fraction decrease occurred in 2.7 percent vs 0.4 percent of patients, with all events in the T-Dxd group being asymptomatic without heart failure.

The preferred ADC in second line HER2-positive mBC treatment

“The key differences of T-Dxd compared with T-DM1 are the improved payload and linker technology. T-Dxd has a higher drug-to-antibody ratio than T-DM1 [approximately 8:1 and 3.5:1, respectively]. Unlike T-DM1, T-Dxd has a tumour-selective cleavable linker, the chemotherapeutic agent is membrane-permeable, and there is evidence of a bystander antitumour effect on neighbouring cells, including HER2-negative cancer cells,” explained discussant Dr Shanu Modi of the Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, US. [Pharmacol Ther 2018;181:126-142] “The bystander effect is particularly important for treatment of HER2-positive breast cancer due to the known heterogeneity of HER2 expression within tumours.”

“Based on results of the DESTINY-Breast03 trial, T-Dxd will be my preferred antibody-drug conjugate [ADC] in second-line treatment of HER2-positive mBC. T-DM1 will be used in the third-line setting,” Modi commented.

“Whether T-DM1 will work after treatment with T-Dxd, what will work as post–T-Dxd treatment, and whether the sequence of T-Dxd therapy affects OS are questions to be answered,” she added.